1. Summer Dewdney, MD Rush University Medical Center

2.  I have nothing to disclose

3.  Cancer genetics  BRCA-associated malignancy  Risk reducing surgery and risks/benefits  Lynch syndrome associated malignancy  Treatment recommendations ◦ “How do I apply this to my practice?”

5.  Cancer is the result of accumulated mutations in DNA either inherited or acquired

6.  Breast  Ovarian/fallopian tube  Colon  Thyroid

7. Knudson, Proc Natl Acad Sci U S A, 1971

8.  Oncogenes ◦ Cause activation  Ras, EGFR  Tumor suppressors ◦ Cause inactivation  p53  DNA repair genes ◦ Repair DS breaks  BRCA, MMR (MLH, MSH,PMS) http://www.cancer.gov/cancertopics/understandingcancer/cancergenomics

9. SyndromeGenes Associated Hereditary Breast Ovarian Cancer BRCA1, BRCA2 Hereditary Non-Polyposis Colon Cancer (HNPCC) aka Lynch Syndrome MLH1, MSH2, MSH6 Cowden SyndromePTEN Familial Adenomatous Polyposis (FAP) APC (Dominant) MYH (Recessive) Li-Fraumeni Syndromep53 Von Hippel-LindauVHL

11. Hereditary Breast and Ovarian Cancer Sporadic Am J Hum Genet 1998; 62:676-89 BRCA1 (52%) Other genes (16%) BRCA2 (32%) 7-10% Hereditary 1/345-800 in general U.S. population 1/40 individuals of Ashkenazi heritage BRCA1 Chromosome 17 ~1200 different mutations reported BRCA2 Chromosome 13 ~1380 different mutations reported

12. SiteGenesLifetime Risk (Est) OvaryBRCA140-66% BRCA210-27% MMR9-12% EndometriumMMR40-60%

13. BRCA1-2 Mutations Increase the Risk of Early-Onset Breast & Ovarian Cancer By age 70By age 50By age 40 Breast cancerPopulation Risk0.50%2%7% BRCA1-210-20%33-50%56-87% Ovarian cancerPopulation Risk0.1%0.3%1% BRCA13%10-21%44% BRCA22%3%27%

14.  Increased risk of ovarian cancer following breast cancer ◦ 10 year risk: 7-13% ◦ Lifetime risk at least 16%  Increased risk of second breast cancer ◦ Within 5 years: 20% ◦ By age 70: 64% JNCI 1999;15:1310-6 J Clin Oncol 1998;16:2417-25 Lancet 1998;351:316-21 J Clin Oncol 1999;17:3396-402 Lancet 1994;3343:692-5

15. Risks of Other Cancers  Male breast cancer (BRCA1, BRCA2) ◦ 6% by age 70  Prostate (BRCA2, ? BRCA1) ◦ 20% by age 80; 3- to 7-fold increase in relative risk  Pancreatic cancer (BRCA2) ◦ 2-3% by age 80; 3- to 4-fold increase in relative risk  Colon ◦ Little or no increased risk  Endometrial ◦ No proven association ◦ UPSC controversial Am J Hum Genet 1997;61: 120-8 JNCI 1999;15:1310-6 Dis Colon Rectum 1999;42:1041-5 Levine DA, et al: Gynecol Oncol 80:395-398; 2001 Beiner ME, et al: Gynecol Oncol 104: 7-10; 2007

16. Ca-125 US OCPs Risk reducing BSO BTL Mammogram MRI Tamoxifen Mastectomy OVARIAN CANCER BREAST CANCER

17.  Breast Cancer Surveillance: ◦ Breast awareness starting at 18yo, clinical BE 25yo q 6-12 mo ◦ Annual mammography/MRI at 25yo  Ovarian Cancer: ◦ RR-BSO 35-40yo or after childbearing OR ◦ TVUS and CA-125 every 6mos at 30yo  Consider chemoprevention NCCN Practice Guidelines in Oncology

18.  Ovarian Cancer Risk ◦ General decrease  HR 0.5 (95% CI; 0.3-0.8) ◦ Greater risk reduction with longer use ◦ Low dose combinations may be more effective  Breast Cancer Risk Controversial Narod, et al. NEJM. 1998; 339: 424-8. Modan et al. NEJM 2001; 345:235-40. Whittemore, et al. Br J CA. 2004; 91:1911-5. Luire G, et al. Obstet Gynecol. 2007 Mar;109(3):597-607 Grimes DA, et al. Am J Obstet Gynecol. 1995; 172:227-35

19.  Chemoprophylaxis ◦ Tamoxifen: 62% reduction in BRCA2+ ◦ BRCA1: no reduction  Mostly ER-/PR- tumors ◦ Decreased risk of contralateral cancer by 75%  Mastectomy ◦ Decreases risk > 90-95% ◦ Contralateral Mastectomy Lancet 2000: 356:1876-81 JNCI 1998; 90:1371-88

20.  Tubal Ligation  Risk Reducing BSO ◦ Reduces risk by ~90% in BRCA mutation carriers ◦ 1-6% risk of primary peritoneal cancer ◦ NIH consensus recommendations (1995):  Recommend prophylactic BSO for high risk woman at age 35, or after childbearing ◦ Patients who choose BSO: older, parous, breast cancer history  Prospective cohort study: Prophylactic BSO associated with: ◦ ↓ overall, OVCA, and breast CA mortality in original analysis ◦ Secondary analysis, only overall mortality significant Schmeler KM et al. Obstetrics & Gynecology, 2006; 515-520 Rebbeck TR, et al: N Engl J Med 346:1616; 2002 Domcheck et al Lancet Oncol 2006;7:223-9

21. Ovarian Cancer Risk Reduction in BRCA1/2 Carriers Breast Cancer Risk Reduction in BRCA1/2 Carriers Rebbeck TR et al. JNCI 2009; 101:80-87

22.  Risk reducing BSO & Breast Cancer Risk ◦ Reduces breast CA risk 40-70% ◦ Protection only if menopausal ◦ Risk reduction greatest before age 40 ◦ Protective effect evident for 15 years post pBSO  HRT following Risk-Reducing BSO ◦ RRSO with short term HRT still associated with a reduction in breast cancer risk in carriers of BRCA1 and BRCA2 mutations. ◦ Limited Data but suggests safe to offer HRT Eisen A et al. J Clin Oncol. 2005 Oct 20;23(30):7491-6. Rebbeck TR et al, JCO 2005. 23:7804-7810.

23.  Ovarian vessel ligation  2 cm IP margin  Remove as much FT as possible  Peritoneal examination + washings  Submit entire specimen for processing with patient history

24. http://www.google.com/search?q=images+laparoscopic+bilateral+salpingo-oophorectomy&source=lnms&tbm=isch&sa=X&ei=diT- U8z5NoKhyAS_hYHwDQ&sqi=2&ved=0CAcQ_AUoAg&biw=1421&bih=802#q=laparoscopic+bilateral+salpingo-oophorectomy

25.  Extensive counseling ◦ Expected cancer risk reduction ◦ Alternatives ◦ Risks of hormonal effects and consequences  Timing of surgery ◦ Generally as soon as childbearing is completed or by age 35-40, recent data BRCA1 age 35 associated with greater benefit  Discuss risk of detecting an occult malignancy, 4-8% ◦ Risk of needing a full staging surgery vs a two staged approach ◦ Recommend pelvic US and +/-CA125

26. Author (N)% with occult cancers % of occult cancers arising from FT Colgan 2001 (60)8.3%80% Leeper 2002 (30)16.7%60% Carcangiu 2006 (50)12%67% Finch 2006 (490)2.2%30% Medeiros 2006 (13)38%100% Rabban 2009 (108)6.5%87.5% Domchek 20102.5%18.8% Powell 2011 (111)9.1%70% Manchanda 2011 (117)8.5%70%

27.  Increasing evidence that ovarian cancers origin is the fallopian tube ◦ Serous tubal intraepithelial carcinoma (STIC) identified in rrBSO specimens ◦ ~70% of high grade serous carcinomas have STICs

28.  GOG 199-completed ◦ Non-randomized trial comparing rrBSO and screening among 2605 women  Many high grade serous carcinomas arise in the FT fimbria rather than ovary  GOG 1206-starting ◦ Assess whether initial bilateral salpingectomy followed by delayed oophorectomy  high risk pre-menopausal women  Reduce risk of cancer and mitigate early hormonal deprivation

29.  McAlpine et al, 2014 Am J Ob Gyn ◦ 2010 in British Columbia, Canada ◦ Started initiative to perform opportunistic salpingectomies ◦ Retrospective review of 43,931 who underwent a hyst +/- BSO  Minimal additional time, NS  No increase risk of complications ◦ Awaiting long term results, need prospective trial for general population

30.  Kwon et al, 2013 Ob Gyn ◦ Developed a Monte Carlo simulation model to compare BSO vs BS vs BS with delayed BO ◦ BS with delayed BO is cost-effective and an acceptable alternative in this model

31.  All ovarian cancer patients NCCN guidelines, 2014

33.  Autosomal dominant cancer susceptibility syndrome  High penetrance Brain<1% 4% Stomach <1% 13% Biliary<1% 2% Small Intestine <1% 5% Urinary Tract<1% 4% Ovarian 1% 12% Endometrial 2% 60% Colorectal 2% 80% General Population Lynch Cancer risk by age 70 Chadwick et al., J Med Genet, 2001, Banno et al., Int J Clin Oncol, 2004

34.  Early but variable age at CRC diagnosis (~45 years)  Proximal colon cancers  Endometrial cancer most common non colon primary ◦ 51% present with Gyn cancer ◦ 49% present with GI cancer ◦ OS similar to sporadic cases Age 50Age 70 Colorectal Cancer Population Risk0%2% HNPCC25%80% Endometrial Cancer Population Risk0.2%1.5% HNPCC20%60% Lu et al Gynecol Oncol 2004; Chadwick et al., J Med Genet, 2001,

35. Features of Lynch Syndrome Sporadic Other lynch syndrome tumors Colorectal or endometrial cancer before 50 Multiple cancers in an individual Multiple generations Increases risk of second malignancy Hereditary Family history of colorectal cancer but not other cancers Later age of onset No clear pattern on one side of the family or the other CRC, 47 CRC, 42 & 51 Endo, 46CRC, 53 CRC, 71 CRC, 63

36. Base pair mismatch Normal DNA repair T C T A C A G C T G T C G A C A G C T G Defective DNA repair (MMR+) T C T A C A G C T G A G A T G T C T A C

37.  Inherited mutation in MMR genes  MLH1, MSH2 mutations responsible for 70-80%  MSH6 mutations in “atypical” HNPCC ◦ Predominance of endometrial cancers ◦ 7-10 years older at diagnosis than in classic Lynch MSH6 (rare) MSH2 ~30% MLH1 ~30% PMS1 (rare) PMS2 (rare) Unknown ~30%

38.  Before genetic testing was available, Lynch Syndrome was identified through defined criteria (“Amsterdam criteria”)  3 relatives with HNPCC-associated cancer  one relative is a 1 st -degree relative of the other two  at least two successive generations  at least one diagnosed < 50 yrs  Many people with mutation-proven Lynch do not meet these criteria J Med Genet 2000;37:641- 5

39. Recommendations for Lynch Syndrome Testing Universal screening on tumor tissue Testing criteria Meets revised Bethesda Guidelines OR Amsterdam criteria Endometrial cancer at <age 50 Known LS in family Consider testing if risk >5% with prediction models NCCN, 2014 criteria

40. Surveillance Options for Carriers of HNPCC-Associated Mutations ASCO/SSO Review of Current Role of Risk-Reducing Surgery in Common Hereditary Cancer Syndromes JCO 2006 Intervention Colonoscopy l Transvaginal ultrasound l Endometrial aspirate Recommendation Begin at age 20–25, repeat every 1–2 years; annually at age 40 Annually, starting at age 30–35 Malignancy Colorectal cancer Endometrial cancer

41.  Two studies of Gynecologic surveillance in HNPCC ◦ Annual or biennial TVS in Lynch syndrome  171 women  No endometrial or ovarian cancers identified over 10 years of follow-up ◦ Annual TVS, CA 125 offered to 41 women who had germline MMR defects or met Amsterdam II criteria  No endometrial or ovarian cancers identified with a median of 5 years of follow-up Cancer 2002; 94: 1708-1712 Gynecol Oncol 2003; 91(1): 74-80

42.  Oral contraceptives decrease the risk of endometrial cancer by 50% in the general population  Progestins investigational  ASA prevention of CRC JAMA 1987;257(6):796-800

43.  Surveillance ◦ Colonoscopy every 1-3 years beginning age 20-25, annually after age 40 ◦ Colonoscopy improves survival and reduces risk of CRC in HNPCC families ◦ Annual transvaginal ultrasound and endometrial aspiration beginning age 25-35  Surgery ◦ Subtotal colectomy for colorectal cancer or advanced adenomas ◦ Consideration of hysterectomy/BSO especially at time of surgery for diagnosed colorectal cancer *Guillem et al. JCO 2006

44.  Screen patients with careful family history  Not everyone has to meet Amsterdam criteria to be suspicious  Carefully consider family history of cancers other than CRC (particularly endometrium, ovary)  Always take note of early onset cancers and synchronous or metachronous cancers  If you suspect inherited cancer susceptibility, offer genetic counseling

45.  Genetic screening should be offered to all ovarian cancer patients  BSO decreases risk of developing ovarian cancer and should be offered to women who are at risk ◦ Pathologic sampling very important to identify occult malignancies  Hysterectomy/BSO should be offered to women with Lynch syndrome after child bearing  Important to take family history to identify women and families at risk